title: Sea anemone peptide with uncommon β-hairpin structure inhibits acid-sensing ion channel 3 (ASIC3) and reveals analgesic activity.
abstract: Three novel peptides were isolated from the venom of the sea anemone Urticina grebelnyi. All of them are 29 amino acid peptides cross-linked by two disulfide bridges, with a primary structure similar to other sea anemone peptides belonging to structural group 9a. The structure of the gene encoding the shared precursor protein of the identified peptides was determined. One peptide, π-AnmTX Ugr 9a-1 (short name Ugr 9-1), produced a reversible inhibition effect on both the transient and the sustained current of human ASIC3 channels expressed in Xenopus laevis oocytes. It completely blocked the transient component (IC50 10 ± 0.6 μM) and partially (48 ± 2%) inhibited the amplitude of the sustained component (IC50 1.44 ± 0.19 μM). Using in vivo tests in mice, Ugr 9-1 significantly reversed inflammatory and acid-induced pain. The other two novel peptides, AnmTX Ugr 9a-2 (Ugr 9-2) and AnmTX Ugr 9a-3 (Ugr 9-3), did not inhibit the ASIC3 current. NMR spectroscopy revealed that Ugr 9-1 has an uncommon spatial structure, stabilized by two S-S bridges, with three classical β-turns and twisted β-hairpin without interstrand disulfide bonds. This is a novel peptide spatial structure that we propose to name boundless β-hairpin.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Osmakov
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozlov
authors.forename: Yaroslav A
authors.initials: YA
authors.lastname: Andreev
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Koshelev
authors.forename: Nadezhda P
authors.initials: NP
authors.lastname: Sanamyan
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sanamyan
authors.forename: Igor A
authors.initials: IA
authors.lastname: Dyachenko
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Bondarenko
authors.forename: Arkadii N
authors.initials: AN
authors.lastname: Murashev
authors.forename: Konstantin S
authors.initials: KS
authors.lastname: Mineev
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Arseniev
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Grishin
mesh_terms: D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012615:Sea Anemones / Q000737:chemistry / Q000235:genetics; D014982:Xenopus laevis
chemical_list: C112231:ASIC3 protein, human; C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D010455:Peptides
keywords: Acid Sensing Ion Channels (ASIC); Gene Structure; Nuclear Magnetic Resonance; Peptides; Protein Chemistry; Protein Purification; Protein Sequence; Protein Structure